KR20070053762A - Lipase inhibitor - Google Patents
Lipase inhibitor Download PDFInfo
- Publication number
- KR20070053762A KR20070053762A KR1020077006215A KR20077006215A KR20070053762A KR 20070053762 A KR20070053762 A KR 20070053762A KR 1020077006215 A KR1020077006215 A KR 1020077006215A KR 20077006215 A KR20077006215 A KR 20077006215A KR 20070053762 A KR20070053762 A KR 20070053762A
- Authority
- KR
- South Korea
- Prior art keywords
- lipase
- food
- lipase inhibitor
- gallic acid
- compound
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical group OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 claims abstract description 29
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
본 발명은, 차 또는 Tellima grandiflora 로부터 분취한 갈로타닌, 엘라기타닌 성분을 함유하는 리파아제 저해제 및 그 저해제를 첨가한 음식료, 의약품을 제공한다. The present invention provides a lipase inhibitor containing gallotanine, an ellagitannin component fractionated from tea or Tellima grandiflora, and a food beverage and a pharmaceutical product to which the inhibitor is added.
본 발명은, 다음 식 Ⅰ: The present invention, the following formula I:
(식 중, R1, R2 및 R3 은 각각 독립적으로 H 또는 갈산 잔기이며, R4 및 R5 는 H 또는 갈산 잔기이거나, 또는 R4 와 R5 는 하나가 되어 다음 식: (Wherein R 1 , R 2 and R 3 are each independently H or gallic acid residues, R 4 and R 5 are H or gallic acid residues, or R 4 and R 5 become one and are of the formula:
로 표시되는 HHDP 기를 형성하지만, Form the HHDP group, but
단, R1 내지 R5 중 적어도 2 개는 갈산 잔기이거나, 혹은 R1, R2 및 R3 이 모두 H 일 때에는 R4 와 R5 는 하나가 되어 HHDP 기를 형성하는 것으로 한다) Provided that R 1 to R 5 At least two of which are gallic acid residues or when R 1 , R 2 and R 3 are all H, R 4 and R 5 become one to form HHDP group)
로 표시되는 화합물의 적어도 일종을 함유하는 리파아제 저해제, 및 그 저해제를 첨가한 음식료, 의약품을 제공한다. Provided are lipase inhibitors containing at least one kind of compound represented by the above, and food and beverage and pharmaceuticals to which the inhibitors are added.
리파아제, 갈로타닌, 엘라기타닌 Lipase, gallotanine, ellagitannin
Description
본 발명은, 차잎 및 Tellima grandiflora 로부터 분취한 갈로타닌, 엘라기타닌 성분으로 이루어지는 리파아제 활성 저해제를 제공한다.This invention provides the lipase activity inhibitor which consists of a galotenin and an ellagitannin component which were fractionated from the tea leaf and Tellima grandiflora.
최근, 일본인의 생활 양식의 구미화에 따라, 고지방식의 섭취가 증가의 일로를 걷고 있다. 1999년 국민 영양 조사에 의하면, 에너지 섭취량은 해마다 감소되고 있음에도 불구하고, 그 지질 에너지 비는 적정 비율인 25% 를 초과하고, 중성 지방치나 콜레스테롤치가 높은 사람의 비율은 60 세 이상에서 5∼6 할로 확인되었다는 보고가 있다 (후생노동성 1999년 국민 영양 조사 결과의 개요 임상 영양 2001; 98(5): 577-588).In recent years, ingestion of the high-fat diet has been on the rise as the Japanese lifestyle has become more and more. According to the 1999 National Nutrition Survey, although the energy intake decreases year by year, the ratio of lipid energy exceeds 25%, which is an appropriate ratio, and the proportion of people with high triglyceride or cholesterol levels is 5-6 halo when they are 60 years old or older. There is a report that has been confirmed (Summary of Ministry of Health, Labor and Welfare 1999 National Nutrition Survey, Clinical Nutrition 2001;
비만은 현대 사회에 있어서의 가장 중대한 질환 중 하나이지만, 그 주된 요인은 지방의 과잉 섭취이다. 또, 지방의 과잉 섭취는, 비만뿐만 아니라, 비만에서 기인되는 당뇨병, 고지혈증, 고혈압, 동맥 경화 등을 발증시키는 것으로 알려져 있다. 이 비만에 대한 치료약으로서, 일본 내에서는, 식욕 억제제의 마진돌 (등록상표) 이 유일하게 승인되고 있지만, 구갈, 변비, 위부 불쾌감, 구역질·구토 등의 부작용이 보고되어 있다 (임상 평가 1985; 13(2): 419-459, 임상 평가 1985; 13(2): 461-515). 또한, 해외에 있어서는, 리파아제 저해 활성에 의해 장관으 로부터의 지방 흡수의 억제 작용을 갖는 제니칼 (등록상표) 이 비만 개선약으로서 시판되고 있지만, 역시 지방변, 배변 수의 증가, 연변(軟便), 설사, 복통 등의 부작용이 보고되어 반드시 안전하다고는 말하기 어렵다 (Lancet 1998; 352: 67-172).Obesity is one of the most serious diseases in modern society, but its main factor is the excessive intake of fat. In addition, excessive intake of fat is known to cause diabetes, hyperlipidemia, hypertension, atherosclerosis, and the like caused by obesity. In Japan, as a treatment for obesity, marginal stones (registered trademark) of an appetite suppressant are approved only in Japan, but side effects such as dry mouth, constipation, stomach discomfort, nausea and vomiting have been reported (clinical evaluation 1985; 13). (2): 419-459, clinical evaluation 1985; 13 (2): 461-515). Overseas, Zenical (registered trademark), which has a lipase inhibitory activity and inhibits fat absorption from the intestine, is commercially available as an obesity improving drug, but also fatty stool, an increase in the number of bowel movements, stool, and diarrhea. And side effects such as abdominal pain have been reported and are not necessarily safe (Lancet 1998; 352: 67-172).
비만을 예방하기 위해서는, 식사 제한에 의해 섭취 칼로리를 줄이는 것이 유효한 수단이기는 하지만, 확실한 영양 지도를 받아야하므로 일상 생활에 있어서의 실행은 곤란한 경우가 많다. 그래서, 식사 유래의 지방이 체내에 흡수되는 것을 안전하고 건강하게 억제하는 것은, 비만 및 여기에 관련된 질환의 치료 혹은 건강 증진의 목적에서, 현실적이며 유용한 방책이라고 생각된다. In order to prevent obesity, reducing calorie intake by dietary restriction is an effective means, but practice in daily life is often difficult because it requires strict nutritional guidance. Therefore, it is thought that safe and healthy suppression of the absorption of diet-derived fat into the body is a practical and useful measure for the purpose of treating obesity and related diseases or improving health.
이러한 배경 아래, 안전하고 또한 인체에 대한 유효성이 증명되어 있는 특정 보건용 식품의 개발이 주목받고 있다. 지금까지 식후의 혈청 중성 지방치의 상승을 억제하는 식품 소재로는, 췌장 리파아제 저해에 의해 지방 흡수를 억제하는 글로빈 단백 분해물 (J. Nutr. 1988; 128: 56-60, 일본 임상·식량 학회지 1999; 52(2): 71-77, 건강·영양 식품 연구 2002; 5(3): 131-144), 트리아실글리세롤과는 상이한 소화 흡수 특성을 갖는 디아실글리세롤 (J. Am. Coll. Nutr. 2000; 19(6): 789-796, Clin. Chim. Acta. 2001; 11(2): 109-117), 어유로부터 정제된 에이코사펜타엔산 (EPA), 도코사헥사엔산 (DHA) 등이 특정 보건용 식품으로서 발매되고 있다. Under this background, the development of certain health foods that are safe and effective for the human body has been attracting attention. To date, food materials that suppress the rise of serum triglyceride levels after meals include globin protein degradation products that inhibit fat absorption by inhibiting pancreatic lipase (J. Nutr. 1988; 128: 56-60, Japanese Clinical and Food Journal 1999; 52 (2): 71-77, Health and Nutrition Food Research 2002; 5 (3): 131-144), diacylglycerols having different digestive absorption properties than triacylglycerols (J. Am. Coll. Nutr. 2000 19 (6): 789-796, Clin. Chim. Acta. 2001; 11 (2): 109-117), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), etc. purified from fish oil; It is released as this specific health food.
식물 유래의 리파아제 저해 활성 물질도 최근 주목받고 있고, 특히, 리파아제 저해 활성을 갖는 폴리페놀류에 관해서는, 식물 수피 유래의 타닌 (일본 특허공보 소60-11912), 콩과 식물 차풀에 함유되는 타닌류나 플라보노이드류 및 그 배당 체 (일본 공개특허공보 평8-259557), 녹차 중의 주요한 성분 에피가로카테킨가레이트 및 에피카테킨가레이트를 배합한 지질 흡수 억제 식품 (일본 공개특허공보 평3-228664), 피망, 시메지 버섯, 호박, 잎새 버섯, 녹미채, 녹차, 우롱차 등의 물 추출물로 이루어지는 리파아제 저해제 (일본 공개특허공보 평3-219872), 플라본 및 플라보놀류 (일본 공개특허공보 평7-61927) 히드록시 벤조산류 (갈산) (일본 공개특허공보 평1-102022), 트리테르펜류 화합물 및 그 유도체 (일본 공개특허공보 평9-40689), 타마린드의 프로시아니딘을 유효 성분으로 하는 항비만제 (일본 공개특허공보 평9-291039) 등이 보고되어 있고, 또 포도 종자 추출물의 리파아제 저해 작용 (Nutrition 2003; 19(10): 876-879), 사라시아 유래 폴리페놀에 의한 리파아제 저해 작용과 래트의 항비만 작용 (J. Nutr. 2002; 132: 1819-1824), 우롱차 추출물에 의한 마우스의 항비만 작용 (Int. J. Obes. 1999; 23: 98-105) 등이 알려져 있다. Plant-derived lipase inhibitory active substances have also attracted attention in recent years. In particular, regarding polyphenols having lipase-inhibiting activity, tannins derived from plant bark (Japanese Patent Publication No. 60-11912), tannins contained in legumes, Flavonoids and its glycosides (Japanese Patent Application Laid-Open No. Hei 8-259557), lipid absorption inhibitory foods containing the main components Epigarocatechin garate and epicatechin garate in green tea (Japanese Patent Laid-Open Application No. Hei 3-228664), bell pepper and shimeji Lipase inhibitors (Japanese Patent Laid-Open Publication No. 3-219872), flavones and flavonols (Japanese Laid-Open Patent Publication Hei 7-61927) consisting of water extracts such as mushrooms, pumpkins, leafy mushrooms, green radish, green tea and oolong tea Benzoic acid (gallic acid) (JP-A-11-102022), triterpene compounds and derivatives thereof (JP-A-9-40689) and tamarind procyanidins Anti-obesity agents (Japanese Patent Application Laid-open No. Hei 9-291039) and the like have been reported, and lipase inhibitory action of grape seed extract (Nutrition 2003; 19 (10): 876-879), caused by polysaccharide derived from sarasia Lipase inhibitory activity and anti-obesity effect of rats (J. Nutr. 2002; 132: 1819-1824), and anti-obesity action of mice by oolong tea extract (Int. J. Obes. 1999; 23: 98-105) Known.
그러나, 위에 나타낸 기보(旣報) 의 식물 유래의 리파아제 저해제는, 효과가 충분한 것이라고는 할 수 없다. 예를 들어, 어느 식물의 추출물에서 효과가 있었다고 해도, 그 안에 함유되는 활성 성분량을 명확하게 하지 않는 한, 천연물이 기원이기 때문에, 안정적으로 리파아제 저해 활성을 유지시키는 것은 곤란하다. 또한, 기호성이 낮은 식물 유래의 저해제의 경우, 음식물로서 이용하기에는, 향미에 영향을 미친다는 문제가 있다. 예를 들어, 우롱차의 지질 개선 효과를 나타낸 보고에는, 시판 우롱차를 1 일 1330㎖ 씩 6 주간 음용시켜, 혈중 중성 지방치의 유의한 저하가 확인되었다는 보고 (일본 영양·식량 학회지 1991; 44(4): 251-259) 나, 단순성 비만증의 남녀 102 명을 대조로, 우롱차 (2g×4/일) 를 6 주간 연속 경구 섭취시킨 결과, 67% 의 피험자에게 1㎏ 이상의 체중 감소가 확인되고, 또한, 혈중 중성 지방치가 높은 값을 나타낸 피험자에 있어서 우롱차 섭취 후에 유의한 개선 효과가 확인되었다는 보고 (일본 임상 영양 학회지 1998; 20(1): 83-90) 가 있다. 이와 같이 우롱차의 대량 음용에서는 효과가 확인되고 있지만, 일상 생활 속에서 계속해 가는 것은 어렵다. 또, 단순하게 농축한 우롱차를 제공했다고 해도, 쓴맛·떫은맛이 강하고, 카페인량도 증가하기 때문에, 현실적인 방책으로서 적당하지 않다. However, the lipase inhibitor derived from the botanicals shown above cannot be said to have sufficient effect. For example, even if it is effective in extracts of certain plants, since natural products are of origin unless the amount of the active ingredient contained therein is clear, it is difficult to stably maintain lipase inhibitory activity. Moreover, in the case of an inhibitor derived from a plant with low palatability, there exists a problem that it affects a flavor to use as food. For example, a report showing the lipid-improving effect of oolong tea reported that a significant decrease in blood triglyceride levels was confirmed by drinking commercial oolong tea 1330 ml / day for 6 weeks (Japanese Nutrition and Food Journal 1991; 44 ( 4): 251-259) B. In contrast to 102 men and women with simple obesity, oolong tea (2g × 4 / day) was taken orally for 6 consecutive weeks, and 67% of subjects found a weight loss of 1 kg or more. In addition, there are reports of significant improvement after oolong tea intake in subjects with high blood triglyceride levels (Japanese Clinical Nutrition Journal 1998; 20 (1): 83-90). Although the effects have been confirmed in the large-scale drinking of oolong tea, it is difficult to continue in daily life. Moreover, even if it provides simply concentrated oolong tea, since bitterness and astringent taste are strong and the amount of caffeine increases, it is not suitable as a realistic measure.
한편, 차 유래 타닌은 그 항산화 활성이 보고되어 있고 (Biosci. Biotechnol. Biochem. 2003; 67(2): 396-401), 식물 유래의 타닌 특히 tellimagrandin 은 항산화 활성 (Phytochemistry 1993; 33(3): 557-561) 뿐만 아니라, 항균성 (Microbiol. I㎜unol. 2004,; 48(1): 67-73) 항암성 (Toxicology Letters 2004; 147(2): 109-119), 사이토카인 방출 조절제 (일본 공표특허공보 2004-510688) 등의 기능이 보고되어 있다. On the other hand, tea-derived tannins have been reported for their antioxidant activity (Biosci. Biotechnol. Biochem. 2003; 67 (2): 396-401), and plant-derived tannins, especially tellimagrandin, have antioxidant activity (Phytochemistry 1993; 33 (3): 557-561) as well as antimicrobial (Microbiol. Immunol. 2004 ,; 48 (1): 67-73) anti-cancer (Toxicology Letters 2004; 147 (2): 109-119), cytokine release modulators (Japan (Patent Publication 2004-510688) and the like have been reported.
특허 문헌 1: 일본 특허공보 소60-11912Patent Document 1: Japanese Patent Publication No. 60-11912
특허 문헌 2: 일본 공개특허공보 평8-259557Patent document 2: Unexamined-Japanese-Patent No. 8-259557
특허 문헌 3: 일본 공개특허공보 평3-228664Patent document 3: Unexamined-Japanese-Patent No. 3-228664
특허 문헌 4: 일본 공개특허공보 평3-219872Patent document 4: Unexamined-Japanese-Patent No. 3-219872
특허 문헌 5: 일본 공개특허공보 평7-61927Patent document 5: Unexamined-Japanese-Patent No. 7-61927
특허 문헌 6: 일본 공개특허공보 평1-102022Patent Document 6: Japanese Patent Application Laid-Open No. 1-02022
특허 문헌 7: 일본 공개특허공보 평9-40689Patent Document 7: Japanese Patent Application Laid-Open No. 9-40689
특허 문헌 8: 일본 공개특허공보 평9-291039Patent Document 8: Japanese Patent Application Laid-Open No. 9-291039
특허 문헌 9: 일본 공표특허공보 2004-510688Patent Document 9: Japanese Patent Application Publication 2004-510688
비특허 문헌 1: 후생노동성 평성 11 년 국민 영양 조사 결과의 개요[Non-Patent Document 1] Summary of 11-year National Nutrition Survey, Ministry of Health, Labor and Welfare
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비특허 문헌 3: 임상 평가 1985; 13(2): 419-459Non Patent Literature 3: Clinical Evaluation 1985; 13 (2): 419-459
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비특허 문헌 5: Lancet 1998; 352: 67-172 Non Patent Literature 5: Lancet 1998; 352: 67-172
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발명의 개시Disclosure of the Invention
발명이 해결하고자 하는 과제Problems to be Solved by the Invention
본 발명은, 식물에 함유되는 다양한 폴리페놀 성분에 착안하여, 차잎 및 Tellima grandiflora 로부터 분취한 갈로타닌, 엘라기타닌 성분의 적어도 일종을 함유하는 리파아제 저해제를 제공한다. The present invention focuses on various polyphenol components contained in plants, and provides lipase inhibitors containing at least one of gallotanine and ellagitannin components fractionated from tea leaves and Tellima grandiflora.
또, 본 발명은, 상기 리파아제 저해제가 첨가되어 향미를 저해하지 않고, 기호성이 높으며, 또한 혈중의 중성 지방 저감, 건강 증진을 목적으로 한 음식료를 제공한다. In addition, the present invention provides a food and beverage for the purpose of reducing the triglycerides in the blood and improving health without adding the lipase inhibitor to inhibit flavor.
또한, 본 발명은 상기 리파아제 저해제를 함유하고, 식사 유래의 지방의 흡수를 억제하여, 혈중 중성 지방의 상승을 억제하는 의약 조성물을 제공한다. The present invention also provides a pharmaceutical composition containing the lipase inhibitor and suppressing the absorption of fat derived from a meal to suppress the rise of triglycerides in the blood.
과제를 해결하기 위한 수단Means to solve the problem
상기 과제를 해결하는 수단으로서, 차 및 Tellima grandiflora 로부터 지방 흡수에 필수적인 췌장 리파아제를 저해하는 성분을 찾아내어, 거기에 존재하는 다양한 폴리페놀의 리파아제 저해 활성을 평가하여, 갈산을 분자 내에 복수 개 갖는 화합물에 강한 리파아제 저해 활성이 있는 것을 밝혀냈다. As a means to solve the above problems, a compound having a plurality of gallic acid in the molecule by finding a component that inhibits pancreatic lipase essential for fat absorption from tea and Tellima grandiflora, evaluating the lipase inhibitory activity of various polyphenols present therein It was found that there is a strong lipase inhibitory activity.
보다 구체적으로는, 본 발명의 리파아제 저해제는, 다음 식 Ⅰ: More specifically, the lipase inhibitor of the present invention is represented by the following formula I:
(식 중, R1, R2 및 R3 은 각각 독립적으로 H 또는 갈산 잔기이며, R4 및 R5 는 H 또는 갈산 잔기이거나, 또는 R4 와 R5 는 하나가 되어 다음 식: (Wherein R 1 , R 2 and R 3 are each independently H or gallic acid residues, R 4 and R 5 are H or gallic acid residues, or R 4 and R 5 become one and are of the formula:
로 표시되는 HHDP 기를 형성하지만,Form the HHDP group, but
단, R1 내지 R5 중 적어도 2 개는 갈산 잔기이거나, 혹은 R1, R2 및 R3 이 모두 H 일 때에는 R4 와 R5 는 하나가 되어 HHDP 기를 형성하는 것으로 한다) Provided that at least two of R 1 to R 5 are gallic acid residues, or when R 1 , R 2 and R 3 are all H, R 4 and R 5 become one to form an HHDP group)
로 표시되는 화합물의 적어도 일종을 유효 성분으로 한다. 또한, 본 명세서 중에서, 갈산 잔기란 카르복실기로부터 OH 가 취해진 갈산의 잔기를 의미한다. At least one kind of compound represented by this is made into an active ingredient. In addition, in this specification, a gallic acid residue means the residue of the gallic acid in which OH was taken from the carboxyl group.
바람직한 유효 성분은, 식 I 에 있어서, R1 내지 R5 중 적어도 3 개는 H 가 아닌 화합물이다. Preferred active ingredients are compounds in which at least three of R 1 to R 5 are not H in the formula (I).
보다 바람직한 유효 성분은, 식 I 에 있어서, R1 내지 R5 중 적어도 4 개는 H 가 아닌 화합물이다. A more preferable active ingredient is a compound in formula I in which at least 4 of R 1 to R 5 are not H.
한 층더 바람직한 유효 성분은, 식 I 에 있어서, R1 내지 R5 의 모두가 H 가 아닌 화합물, 예를 들어 R1, R2 및 R3 의 모두가 갈산 잔기이며, R4 와 R5 는 하나가 되어 HHDP 기를 형성하는 화합물 (화합물 8) 이다. One more preferred active ingredient is a compound wherein, in Formula I, all of R 1 to R 5 are not H, for example, all of R 1 , R 2 and R 3 are gallic acid residues, and R 4 and R 5 are one To form an HHDP group (compound 8).
본 발명의 리파아제 저해제에 함유되는 구체적 화합물의 예로서, 도 1 에 나타내는 화합물을 들 수 있다. As an example of the specific compound contained in the lipase inhibitor of this invention, the compound shown in FIG. 1 is mentioned.
리파아제 저해제Lipase inhibitors
본 발명의 리파아제 저해 활성 화합물은, 다른 성분을 함유하지 않고 단독으로 리파아제 저해제로서 사용할 수도 있고, 또는 용매나 고체 담체와 함께 리파아제 저해제로서 사용하는 것이 가능하다. 용매 또는 담체는, 하기 음식료 및/또는 의약품으로서의 사용을 생각하여, 식품으로서 또는 의약품으로서 안전하게 사용할 수 있는 것이 바람직하다. 본 발명의 리파아제 저해제는 다양한 용도를 가져, 예를 들어 시험 연구용, 중성 지방의 축적을 예방하기 위한 식품, 의약품의 유효 성분으로서의 사용이 예시된다. The lipase inhibitory active compound of the present invention may be used alone as a lipase inhibitor without containing other components, or may be used as a lipase inhibitor with a solvent or a solid carrier. It is preferable that a solvent or a carrier can be used safely as a food or a medicine in consideration of the use as the following food and beverage and / or a medicine. The lipase inhibitors of the present invention have a variety of uses, for example, for use in test studies, as an active ingredient in foods and pharmaceuticals to prevent the accumulation of triglycerides.
리파아제 저해 활성 측정 방법Method for measuring lipase inhibitory activity
본 발명의 리파아제 저해제는, 리파아제, 특히 췌장 리파아제에 대한 강한 저해 작용을 갖는다. 그 저해 활성은, 실시예 1 에 구체적으로 기재하는 방법으로 측정할 수 있다. Lipase inhibitors of the present invention have a strong inhibitory action against lipases, in particular pancreatic lipases. The inhibitory activity can be measured by the method specifically described in Example 1.
리파아제 저해제 함유 음식료Food and drink containing lipase inhibitor
본 발명의 리파아제 저해제를, 음식료에 첨가하여, 식사로부터의 지방분의 섭취에 수반하는 혈중 중성 지방의 바람직하지 않은 상승을 방지하고, 및/또는 상승한 혈중 중성 지방을 저감시킬 수 있다. 음식료의 바람직한 예는, 일상적으로 섭취하는 음식료, 예를 들어, 녹차, 보리차, 우롱차, 홍차, 커피, 스포츠 드링크, 음료수, 조미료, 드레싱이다. 그러나 음식료는, 통상 먹는 것이면 좋고, 청량 음료, 칵테일, 맥주, 위스키, 소주, 와인, 청주, 조미료, 드레싱, 양념미, 가공 식품, 인스턴트 식품, 레토르트 식품, 초콜릿, 생크림, 양과자, 유제품, 건강 식품, 서플리먼트 등이어도 된다. The lipase inhibitor of the present invention can be added to food and drink to prevent undesired rise of triglycerides in the blood accompanying ingestion of fat from meals and / or reduce elevated triglycerides in the blood. Preferred examples of the food and drink are food and drink ingested daily, for example, green tea, barley tea, oolong tea, black tea, coffee, sports drinks, beverages, seasonings, dressings. But food and drink should just eat normally, soft drink, cocktail, beer, whiskey, shochu, wine, sake, seasoning, dressing, seasoning, processed food, convenience food, retort food, chocolate, fresh cream, confectionery, dairy product, healthy food Or a supplement may be used.
음식료에 대한 본 발명의 리파아제 저해제의 첨가량은, 1 끼당 유효 성분의 섭취량이 0.1mg∼10g 이 되도록 첨가한다. 단, 본 발명의 리파아제 저해제는, 식품에 유래하기 때문에, 안전성이 매우 높아, 음식료에 대한 첨가량에 실질적 상한은 없다. The amount of the lipase inhibitor of the present invention added to the food and drink is added so that the intake amount of the active ingredient per meal is 0.1 mg to 10 g. However, since the lipase inhibitor of the present invention is derived from food, the safety is very high, and there is no substantial upper limit to the amount of the lipase added to the food and beverage.
리파아제 저해제 함유 의약품Drugs containing lipase inhibitors
본 발명의 리파아제 저해제는, 식사 유래의 지방의 흡수를 억제하고, 혈중 중성 지방의 바람직하지 않은 상승을 방지 및/또는 저하시키기 위한 약제의 유효 성분으로서도 사용할 수 있다. 바람직한 약제는, 경구 투여되는 약제이며, 그 예로, 드링크제, 정제, 캡슐제, 과립제, 산제, 캔디, 드롭제 등을 들 수 있다. 약제에 함유되는 본 발명의 리파아제 저해제의 양은, 1 회 복용량당, 0.1mg∼10g 이다. The lipase inhibitor of the present invention can also be used as an active ingredient of a medicament for inhibiting absorption of fats derived from meals and preventing and / or lowering undesirable rise of triglycerides in the blood. Preferred medicaments are medicaments administered orally, and examples thereof include drinks, tablets, capsules, granules, powders, candy, and drops. The amount of the lipase inhibitor of the present invention contained in the drug is 0.1 mg to 10 g per dose.
본 발명의 의약품은, 리파아제 저해 성분의 안전성이 높기 때문에, 장기간에 걸쳐서 복용해도 안전하다. 따라서, 생활 습관병으로서의 비만의 방지 또는 해소를 위해, 일상적으로 복용하는 것도 가능하다. Since the drug of the present invention has high safety of the lipase inhibitory component, it is safe even if taken over a long period of time. Therefore, in order to prevent or eliminate obesity as a lifestyle disease, it is also possible to take it routinely.
발명의 효과Effects of the Invention
본 발명은, 차잎 및 Tellima grandiflora 에서 유래되는 갈로타닌 및 엘라기타닌 성분의 적어도 일종을 함유하는 리파아제 저해제를 첨가하여, 향미를 저해하지 않고, 기호성이 높으며, 또한 중성 지방 저감, 건강 증진을 목적으로 한 음식료를 제공할 수 있다. 식사성 지방의 흡수를 억제하기 위해서는, 식사와 함께 섭취하는 것이 바람직하고, 차로부터 얻어진 유효 성분을 강화한 음료는 의의가 크다. 특히, 이들 성분을 증강시킴으로써, 항비만 작용, 건강 증진을 목적으로 한 음료의 제공이 가능하게 되었다. The present invention adds a lipase inhibitor containing at least one of gallotanine and ellagitannin components derived from tea leaves and Tellima grandiflora, and does not inhibit flavor, has high palatability, and aims to reduce triglycerides and improve health. One can provide food and drink. In order to suppress absorption of dietary fat, it is preferable to take it with a meal, and the drink which strengthened the active ingredient obtained from tea is significant. In particular, by enhancing these components, it is possible to provide a beverage for the purpose of anti-obesity action and health promotion.
도면의 간단한 설명Brief description of the drawings
도 1 은, 실시예 5 에서 리파아제 저해 활성 평가에 이용한 화합물의 화학 구조식을 나타낸다. 1 shows chemical structural formulas of compounds used for lipase inhibitory activity evaluation in Example 5. FIG.
실시예 1 리파아제 저해 활성의 측정 Example 1 Measurement of Lipase Inhibitory Activity
리파아제 활성의 측정은, 기질에 형광성의 4-메틸운베리페론의 올레산에스테르 (4-UMO) 를 사용하여, 반응에 의해 생성된 4-메틸운베리페론의 형광을 측정함으로써 실시했다. The measurement of the lipase activity was performed by measuring the fluorescence of 4-methyl unberiferone produced by the reaction using fluorescent oleic acid ester (4-UMO) of 4-methyl unberiferon as a substrate.
측정에 있어서, 완충액은, 150mM NaCl, 1.36mM CaCl2 를 함유하는 13mM Tris-HCl (pH8.0) 을 이용했다. 기질인 4-UMO (Sigma 사 제조) 는 0.1M 의 DMSO 용액으로서 제조한 것을 상기 완충액으로 1000 배희석한 것을, 또한, 리파아제는 돼지 췌장 리파아제 (Sigma 사 제조) 를 동일하게 상기 완충액을 이용하여 400U/㎖ 용액으로서 조제한 것을 효소 측정에 제공했다. In the measurement, 13 mM Tris-HCl (pH 8.0) containing 150 mM NaCl and 1.36 mM CaCl 2 was used as the buffer. 4-UMO (manufactured by Sigma), which is a substrate, was prepared as 0.1 M DMSO solution by 1000 times dilution with the buffer, and lipase was 400 U using the same buffer as pig pancreatic lipase (manufactured by Sigma). What was prepared as / mL solution was used for the enzyme measurement.
효소 반응은, 25℃ 조건 하에서, 96 웰 마이크로플레이트에 50㎕ 의 4-UMO 완충액 용액, 25㎕ 의 증류수 (혹은 시료 수용액) 를 첨가하여 혼합한 후에, 25㎕ 의 리파아제 완충액 용액을 첨가함으로써 개시시켰다. 30 분간 반응을 실시한 후에, 100㎕ 의 0.1M 시트르산 완충액 (pH4.2) 을 첨가하여 반응을 정지시키고, 반응에 의해 생성된 4-메틸운베리페론의 형광 (여기 파장 355㎚, 형광 파장 460㎚) 을 형광 플레이트 리더 (Labsystems 사 제조 Fluoroskan Asent CF) 를 이용하여 측정했다. The enzyme reaction was initiated by adding 50 μl of 4-UMO buffer solution and 25 μl of distilled water (or sample solution) to a 96 well microplate under 25 ° C., followed by addition of 25 μl of lipase buffer solution. . After the reaction was carried out for 30 minutes, the reaction was stopped by adding 100 µl of 0.1 M citric acid buffer (pH4.2), and the fluorescence (excitation wavelength 355 nm, fluorescence wavelength 460 nm) of 4-methylunberiferone produced by the reaction was stopped. ) Was measured using a fluorescent plate reader (Fluoroskan Asent CF manufactured by Labsystems).
피험 시료의 저해 활성은, 대조 (증류수) 의 활성에 대해서 50% 를 저해하는 시료량 IC50 (μM) 으로서 구했다. The inhibitory activity of the test sample was determined as a sample amount IC 50 (μM) that inhibits 50% of the control (distilled water) activity.
측정 샘플Measure sample
갈산 (Gallic acid) (화합물 1) 는 나칼라이 테스크로부터 구입했다. 화합물 2, 3, 4, 5 는 하시모토 들의 논문 (Chem. Pharm. Bull. 1989; 37(12): 3255-3563, Chem. Pharm. Bull. 1989; 37(1): 77-85) 방법에 의해 우롱차로부터 정제했다 (실시예 2). 1,2,4,6-테트라갈로일글루코오스(1,2,4,6-tetragalloylgluco se) (화합물 6) 는 실시예 3 의 방법으로 Camellia ptilophylla 로부터 정제했다. Tellimagrandin 류 (화합물 7,8) 는 실시예 4 의 방법으로 Tellima grandiflora 로부터 정제했다.Gallic acid (Compound 1) was purchased from Nacalai task.
실시예 2 갈로타닌류 2,3,4,5 의 정제 Example 2 Purification of
화합물 2, 3, 5 는 하시모토 등의 논문 (Chem. Pharm. Bull. 1989; 37(12): 3255-3563) 의 방법에 의해 정제했다. 이하에 간단하게 그방법을 나타낸다. 우롱차 잎을 80% 아세톤으로 추출한 후, 아세톤을 제거하고, 세파덱스 LH-20 (팔마시아사 제조) 으로 물, 메탄올, 50% 아세톤을 이용하여 분획을 실시했다. 물-메탄올 용출 획분을 MCl-gel CHP-20P (미츠비시 화학사 제조) 로 물-메탄올 용출을 실시한 후 재차, 세파덱스 LH-20 (팔마시아사 제조) 에 부하하여 수용출에서 화합물 2 및 3 을 얻었다. 물-메탄올 용출 획분을 세파덱스 LH-20 (팔마시아사 제조) 으로 물-메탄올 용출 후, Fuji gel ODS-G3 (후지 실리시아 화학사 제조) 으로 물-메탄올 용출 후 용출을 실시하여, 화합물 5 를 얻었다.
또한 화합물 4 는 논문 Chem. Pharm. Bull. 1989; 37(1): 77-85 의 방법으로 다음과 같이 하여 정제했다. 우롱차 잎을 80% 아세톤으로 추출한 후, 아세톤을 제거하고, 세파덱스 LH-20 (팔마시아사 제조) 으로 물, 메탄올, 50% 아세톤을 이용하여 분획을 실시했다. 메탄올 용출물을 MCl-gel CHP-20P (미츠비시 화학사 제조) 로 물-메탄올 용출을 실시한 후, Bondapak C18 (워터즈사 제조) 로 물 메탄올 용출, 다시 세파덱스 LH-20 (팔마시아사 제조) 으로 에탄올 용출을 실시하여, 화합물 4 를 얻었다.
실시예 3 1,2,4,6-tetragalloylglucose (화합물 6) 의 정제Example 3 Purification of 1,2,4,6-tetragalloylglucose (Compound 6)
Camellia ptilophylla 의 잎 (건조물) 100g 을 2000㎖ 의 열수 (90℃) 에서 4 분간 추출하여 동결 건조시킨 것을 이용하여 이하와 같이 정제를 실시했다. 동결 건조 분말의 1% 수용액을 Sep-Pak C18 Cartridge (5㎖, 워터즈사 제조) 에 흡착시켜, 이것을 물 세정한 후, 아세토니트릴에 의해 용출하는 획분을 동결 건조시켰다. 이 획분, 250㎎ 을 Develosil C30-UG-5 (20㎜ x 250㎜, 노무라화학사 제조) 에 부하하고, 0.05% TFA 존재 하, 5-30% 아세토니트릴의 직선 구배 (5㎖/min, 180min) 에 있어서 용출시켜, A280㎚ 의 흡수를 모니터하면서 분획했다. 얻어진 획분을 이어서 YMC-Pak ODS (20㎜ x 250㎜, 와이엠씨사 제조) 에 부하하고, 0.1% TFA 존재 하, 20-25% 아세토니트릴의 직선 구배 (6㎖/min, 60min) 에 있어서 용출시켜 정제를 실시하여, 1,2,4,6-tetragalloylglucose (화합물 6) 를 얻었다. 100 g of leaves (dried) of Camellia ptilophylla were extracted for 4 minutes in 2000 ml of hot water (90 ° C.) and lyophilized to purify as follows. A 1% aqueous solution of the lyophilized powder was adsorbed onto a Sep-Pak C18 Cartridge (5 ml, manufactured by Waters). After washing with water, the fraction eluted with acetonitrile was lyophilized. This fraction, 250 mg, was loaded onto Develosil C30-UG-5 (20 mm × 250 mm, manufactured by Nomura Chemical Co., Ltd.), and a linear gradient of 5-30% acetonitrile in the presence of 0.05% TFA (5 ml / min, 180 min) Was eluted at and fractionated while monitoring the absorption at A280 nm. The obtained fractions were then loaded into YMC-Pak ODS (20 mm × 250 mm, manufactured by YMC Corporation) and eluted in a linear gradient of 20-25% acetonitrile (6 ml / min, 60 min) in the presence of 0.1% TFA. Purification was carried out to obtain 1,2,4,6-tetragalloylglucose (Compound 6).
실시예 4 Tellimagrandin 류의 정제 Example 4 Tablets of Tellimagrandin Family
Phytochemistry 1976; 15: 211-214 에 준하여 이하와 같이 추출 정제를 실시했다. Tellima grandiflora 의 잎 100g 을 액체 질소 중에서 분쇄하고, 1000㎖ 의 50% 에탄올에서 추출하여, 용매를 증류 제거 후, 흡착 수지 HP-20 (미츠비시 화학사 제조) 에 부하하여 물 세정한 후, 아세토니트릴에 의해 용출하는 획분을 동결 건조시켰다. 이 획분을 Develosil ODS-UG-5 (50㎜ x 500㎜, 노무라 화학사 제조) 에 부하하고, 0.05% TFA 존재 하, 5-25% 아세토니트릴의 직선 구배 (32㎖/min, 80min) 에 있어서 용출시키고, A260㎚ 의 흡수를 모니터하면서 분획하여, Tellimagrandin 1 및 Tellimagrandin 2 를 얻었다. Phytochemistry 1976; 15: According to 211-214, extraction purification was performed as follows. 100 g of leaves of Tellima grandiflora were pulverized in liquid nitrogen, extracted with 1000 ml of 50% ethanol, the solvent was distilled off, loaded on adsorption resin HP-20 (manufactured by Mitsubishi Chemical Co., Ltd.), washed with water, and washed with acetonitrile. The eluting fractions were lyophilized. This fraction was loaded onto Develosil ODS-UG-5 (50 mm x 500 mm, manufactured by Nomura Chemical Co., Ltd.) and eluted in a linear gradient of 5-25% acetonitrile (32 ml / min, 80 min) in the presence of 0.05% TFA. And fractionating while monitoring the absorption of A260 nm,
실시예 5 리파아제 저해 활성Example 5 Lipase Inhibitory Activity
차 유래의 가로카테킨류 및 tellimagrandin 류 (엘라기타닌) 의 리파아제 저해 활성을 표 1 에 나타냈다. 구조 활성 상관을 검토하기 위해, IC50 값은 μM 으로 표기했다. 또한, 도 1 에는 평가에 이용한 화합물의 화학 구조식을 기재했다. Table 1 shows the lipase inhibitory activity of the tragacatechins and tellimagrandin (elagitannin) derived from tea. In order to examine the structural activity correlations, IC 50 values were expressed in μM. In addition, the chemical structural formula of the compound used for evaluation was described in FIG.
이들 타닌 중에서 리파아제 저해 활성을 나타낸 것은, 갈산이 당에 3 분자 이상 결합되어 있는 화합물 (화합물 4,6) 및 HHDP 기가 결합된 엘라기타닌류 (화합물 5,7,8) 이었다. 갈산이나 갈산을 1 분자밖에 갖지 않는 배당체는 활성이 없었다. 갈산이 많아질수록 리파아제 저해 활성이 강해지는 점에서 활성 발현에는 분자 내의 적어도 두 개의 갈레이트기의 존재가 필요하다는 것이 판명되었다. Among these tannins, lipase inhibitory activity was shown to be a compound in which gallic acid was bound to sugar by at least 3 molecules (
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JP2010222276A (en) * | 2009-03-23 | 2010-10-07 | Kao Corp | Postprandial blood triglyceride concentration rise inhibitor |
US8247003B2 (en) * | 2009-08-07 | 2012-08-21 | Muhammed Majeed | Protective compositions for dermal papilla cells |
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CN108451959B (en) * | 2015-06-10 | 2021-04-20 | 苏州禾研生物技术有限公司 | Application of galloylglucoside derivatives and pharmaceutical composition for treating hyperuricemia |
US20190290671A1 (en) * | 2018-03-26 | 2019-09-26 | Muhammed Majeed | Hypolipidemic effects of compositions comprising beta-glucogallin |
CN110354135A (en) * | 2019-07-26 | 2019-10-22 | 江苏省中国科学院植物研究所 | Tetra- galloyl glucose ester of 1,2,3,6- is preparing the application on lipase inhibitor drug or health food |
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